Design, Synthesis, and Antiviral Activity of α-Nucleosides:  d- and l-Isomers of Lyxofuranosyl- and (5-Deoxylyxofuranosyl)benzimidazoles

• Published in: Journal of medicinal chemistry Vol. 41; no. 8; pp. 1242 - 1251
• Main Authors: Migawa, Michael T., Girardet, Jean-Luc, Walker, John A., Koszalka, George W., Chamberlain, Stanley D., Drach, John C., Townsend, Leroy B.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.04.1998; Amer Chemical Soc
• Subjects: a-Nucleosides; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; benzimidazole; benzimidazoles; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Cell Division - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Cytomegalovirus - drug effects; Cytomegalovirus - growth & development; Drug Design; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Fibroblasts - drug effects; Fibroblasts - virology; Herpes simplex virus 1; Herpesvirus; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - growth & development; Human cytomegalovirus; Humans; KB Cells; Life Sciences & Biomedicine; Medical sciences; Microbial Sensitivity Tests; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pentoses - chemical synthesis; Pentoses - chemistry; Pentoses - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Skin - cytology; Skin - drug effects; Skin - virology; Stereoisomerism; Structure-Activity Relationship; Viral Plaque Assay; CIDOFOVIR; 5-DEOXYPENTOSES; BENZIMIDAZOLE RIBONUCLEOSIDES; ZIDOVUDINE; GANCICLOVIR; CYTOMEGALOVIRUS; DERIVATIVES; HERPES-SIMPLEX VIRUS; 5-O-METHYLPENTOSES; Antineoplastic agent; Stereoisomer; Herpesviridae; Alphaherpesvirinae; Cytotoxicity; Betaherpesvirinae; In vitro; Human cytomegalovirus; Virus; Herpesvirus hominis 1; Structure activity relation; Benzimidazole derivatives; Chlorine Organic compounds; KB cell line; Established cell line; Antiviral; Nucleoside; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970545c

Several 2-substituted α-d- and α-l-lyxofuranosyl and 5-deoxylyxofuranosyl derivatives of 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)benzimidazole (1263W94) and 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) were synthesized and evaluated for activity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxicity against HFF and KB cells. Condensation of 1,2,3,5-tetra-O-acetyl-l-lyxofuranose (2a) with 2,5,6-trichlorobenzimidazole (1) yielded the α-nucleoside 3a. The 2-bromo derivative and 2-methylamino derivative were prepared by treatment of 3a with HBr followed by deprotection or from methylamine, respectively. Compound 3a was deprotected and the resultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopropylamino derivatives. The 2-alkylthio nucleosides were prepared by condensing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprotection. Alkylation of this adduct gave the 2-methylthio and 2-benzylthio derivatives. Condensation of 5-deoxy-1,2,3-tri-O-acetyl-l-lyxofuranosyl, prepared from l-lyxose, with 1 or 2-bromo-5,6-dichlorobenzimidazole (15), followed by deprotection, gave the 2-chloro or 2-bromo-5‘-deoxylyxofuranosyl derivative, respectively. The cyclopropylamino derivative was prepared from the 2-chloro derivative. All d-isomers were prepared in an analogous fashion from d-lyxose. Either compounds were inactive against HSV-1 or weak activity was poorly separated from cytotoxicity. In contrast, the 2-halogen derivatives in both the α-lyxose and 5-deoxy-α-lyxose series were active against the Towne strain of HCMV. The 5-deoxy α-l analogues were the most active, IC50's = 0.2−0.4 μM, plaque assay; IC90's = 0.2−2 μM, yield reduction assay. All of the 2-isopropylamino or 2-cyclopropylamino derivatives were less active (IC50's = 60−100 μM, plaque assay; IC90's = 17−100 μM, yield reduction assay) and were not cytotoxic. The methylamino, thio, and methylthio derivatives were neither active nor cytotoxic. The benzylthio derivatives were weakly active, but this activity was poorly separated from cytotoxicity. The α-lyxose l-isomers were more active in a plaque assay against the AD169 strain of HCMV compared to the Towne strain, thereby providing additional evidence of antiviral specificity.